Information Integration
Very little happens anywhere in
the human body without the brain playing a part by monitoring the situation and
exerting its influence. The brain can thus be expected to have a critical role
in regulating weight through its direction of appetite, motivation and physical
activity, as well as its management of how energy is allocated within the body.
Indeed, a small region at the
base of the brain called the hypothalamus has been known for many years to be
central to these energy-regulating activities. In animal studies, placing tiny
lesions in this area can cause obesity or leanness depending on their precise
location. Such observations have led to certain parts of the hypothalamus being
labeled as "satiety" or "feeding" centers.
By stimulating appetite or the
feeling of satiety, the brain can directly manage the body's energy balance
from day to day. Over longer periods, signaling from the brain can also
suppress nonessential systems, such as growth and reproduction, when fat stores
are too low and energy must be conserved for survival. For the brain to command
any of these mechanisms in response to the body's needs, however, it must
receive updated information about how much stored energy is available.
What might this signal be, and
how might it work? Many different molecules have been shown to influence
appetite as their levels in the bloodstream rise and fall, including various
breakdown products of food, such as glucose, and gut-derived hormones, such as
insulin and cholecystokinin (CCK). But a critical regulator of how much energy
is maintained in storage proved elusive until Jeffrey Friedman of the
Rockefeller University and his colleagues discovered leptin in 1994.
Decades earlier a spontaneous
syndrome of severe obesity with increased appetite and decreased energy
expenditure appeared in certain mice bred at the Jackson Laboratory in Maine.
Because a mouse had to inherit the trait from both parents, the syndrome itself
was called ob/ ob. Despite hundreds of studies attempting to understand obesity
in these mice, Friedman's group was the first to identify the inherited gene
mutation responsible. The researchers also determined that the newly identified
gene was predominantly active in fat cells and gave rise to a protein that was
not made in functional form in the mice harboring the ob mutation. The obesity
syndrome seemed to be caused by the absence of this substance.
The researchers named the protein
leptin, from the Greek root leptos, for "thin," and quickly
demonstrated that replacing the missing leptin by daily injections lowered the
weight of affected mice by reducing their appetite and increasing their energy
expenditure. Very soon, others furthered this remarkable discovery by finding a
similar loss-of-function mutation in the human leptin gene among people with
extremely rare cases of severe, early-onset obesity. Administering leptin to
these subjects helped them to lose weight just as it had the mice.
These experiments demonstrated
for the first time a physiological system whereby fat cells produce a hormonal
signal that reflects their state of energy storage--the more triglyceride a fat
cell contains, the more leptin it generates--and to which the brain responds by
altering appetite and energy expenditure. When this energy-status signal is
absent, either because the genetic mutation prevents functional leptin proteins
from being manufactured or because the body actually has low fat stores, the
brain believes that the body is starving and behaves accordingly by promoting
hunger and energy conservation.
The discovery of leptin opened
the door to exploration of a whole new biological pathway of cellular signaling
and responses. The brain was clearly a major target of leptin secreted into the
bloodstream by fat cells, and researchers, including ourselves, have begun to
learn many of the detailed neural circuits and cell types through which leptin
acts. As might be expected, many of them are in the hypothalamus.
In a structure called the arcuate
nucleus of the hypothalamus, within the area previously identified as a satiety
center, leptin simultaneously affects two neighboring neuron populations that
control appetite in opposite ways. One set of neural cells produces a peptide
called alpha-MSH that reduces appetite and, consequently, body weight. The
other set of neurons produces two neuropeptides, NPY and AgRP, both of which
stimulate feeding and promote obesity. Leptin's interactions with both these
cell groups are quite elegant. Neurons that produce MSH connect to neurons
elsewhere in the hypothalamus that carry a surface protein known as the
melanocortin 4 receptor (MC4R), whose activation reduces appetite and promotes
weight loss. AgRP, the peptide that promotes feeding, is an antagonist of this
receptor, meaning that it prevents receptor activation. Thus, leptin acts to
trigger MC4 receptors both by stimulating them directly via the MSH-producing
neurons and by inhibiting their antagonist.
At the same time, leptin also affects
the brain area previously viewed as a feeding center, the lateral hypothalamus,
in an interesting way. One group of cells in that region produces a small
protein called melanin-concentrating hormone (MCH). In 1996 our research group
discovered that levels of this peptide are raised in the ob/ob mouse type,
suggesting that leptin normally inhibits production of the peptide. We also
established that increased MCH promotes food intake and obesity and found that
even ob/ ob mice, if they lack the ability to manufacture MCH, are
substantially less obese. We had thus found another clear example of the
physiological system through which leptin acts as a signal that regulates
hypothalamic neuropeptides, which in turn exert control over appetite and
energy balance.
The same cells and circuits
affected by leptin, moreover, are also acted on by numerous other circulating
factors. The hypothalamus and related brain areas integrate all this
information coming from diverse sources to produce a real-time picture of the
body's energy status and orchestrate responses to manage energy resources. For
a better understanding of what these signals, including leptin, are telling the
brain, researchers are also studying how and where they originate.
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